Chronic pain represents a major unmet clinical need. Studies in our lab are designed to identify molecular mechanisms of sensitization in pain pathways with the goal of identifying novel targets for analgesic intervention. Studies performed under the two previous terms of this grant identified a critical signaling cascade in spinal cord dorsal horn neurons that underlies central pain sensitization. This pathway is initiated by mGlu5 activation of extracellular signal-regulated kinase (ERK1/2) signaling, leading to phosphorylation of a Kv4.2- containing K+ channels, resulting in enhanced excitability of dorsal horn neurons. This increase in excitability likely contributes to central sensitization associated with persistent pain. The studies proposed here will test whether modulation of neuronal excitability and nociceptive behaviors by mGlu5 requires ERK2 (and not ERK1), and whether this is a direct result of phosphorylation of Kv4.2 at a functionally identified phosphorylation site. We will also test the potential clinical utility of fenobam, a clinically validated selective mGlu5 antagonist. We will initially test whether tolerance to the analgesic actions of this drug develops with repeated dosing. Finally, we will take our findings of a key role for mGlu5 in central pain sensitization from the laboratory to the clinic by initiating human trials and asking whether an mGlu5 antagonist can reverse central sensitization in healthy volunteers. PUBLIC HEALTH RELEVANCE: Central sensitization is a term that describes changes in the central nervous system that lead to enhanced pain in the context of injury. Central sensitization is believed to important in the development of chronic pain, and this grant seeks to understand the molecular mechanisms that mediate central sensitization. Also proposed is a study testing whether a drug that reverses central sensitization in animal models can also reverse central sensitization, and thus pain hypersensitivity, in an experimental pain model in healthy human subjects.